Delta1-androstendione and a process of making the same



Patented May 18, 1948 Ar-ANDROSTENDIONE AND A PROCESS OF MAKING THE SAME Adolf ButenandhBerlin-Dahlem, Germany, as-

aignor to sobering Corporation, Bloomfield, N. 1., a corporation of New Jersey No Drawing. Application July so, 1940, Serial No. 848,450. In Germany August 2, 1939 11 Claims. (01. etc-391.3) I

This invention relates to A1-3-keto steroids, and particularly to Ai-androstendione, and to a process of making the same.

It is already known that on treating 3-oxo derivatives of steroids, in which the nuclei A and Bare connected with each other in trans-position according to Formula I. with one mol of halogen, such as bromine, preferentially 2- halogen derivatives oi said ketones corresponding to Formula II are obtained. By this method. among others, 2-bromo cholestanone (Ha), 2- bromo-3-oxo bis-nor-allo cholenic acid (11b) 2- bromo-allo-pregnandione ,(IIc) and z-bromoandrostandione (IId) have been prepared and It is further known that on treating said bromo ketones with agents capable of splitting ofi halogen hydride, for example, with potassium acetate in a solution 01 glacial acetic acid, a s-unsaturated ketones are obtained, which have been regarded as Iii-unsaturated derivatives of steroids corresponding to Formula 111: 1

OH: CHI

II R -01H R -COCHI R-zO Now, it has been found that Ai-unsaturated steroid ketones-3 of another structurethan that hitherto known are obtained from said z-halogenated 3-keto steroids by splitting oi! halogen hydride, such as hydrogen bromide, at elevated temperature in the presence of higher boiling bases of the pyridine group, especially oi collidine.

Thus, on boiling 2-bromo androstandione with 2 collidine the Ai-androstendione of M, P. 138139 C. is obtained. The same compound is also formed on boiling 2-bromo-cholestanone with collidine, whereby Ai-cholestenone of M. P. 95 C. is obtained, and subsequently splitting oil! the side chain in 17-positlon by known methods, thereby yielding a keto group in 17-position. Likewise by boiling 2-bromo-allo-pregnandione with collidine Ai-allo-pregnendione is obtained which also may be transformed into Ai-androstendione of M. P. 138-139 C. by degradation methods known per se. In the same manner other A1- unsaturated steroid ketones may be prepared and converted into Ai-androstendione.

This compound has an excellent physiological activity, for it has proved to be a highly active male sex hormone. On testing the same according to Butenandt and Tscherning by subcutaneous injection of its solution in sesame 011, two times 807 cause an increase or the area of the capons comb of about 20%. In the smear test accordin to Fussganger 5 times 0.5 directly applied on the capons comb were sufilcient to cause an increase of the .area of the comb or about Thus, while, on testing this product accordin to Butenandt in subcutaneous application, the activity or ni-androstendlone is about /3 0f the activity of testosterone, it belongs to the most active compounds of the androsterone series hitherto known when tested according to Fussginger.

The following examples illustrate the invention without, however, limiting the same to them.

Example 1 2.68 gs. of 2-bromo-cholestanone are boiled with 20 cos. of collidine for 2 hours. After cooling, the solution is poured into dilute hydrochloric acid and extracted with ether. The ethereal solution is washed with dilute hydrochloric acid, then with water. dried with sodium sulfate and concentrated by evaporation. The oily residue crystallizes on cooling. It is recrystallized from acetone or from alcohol. From dilute acetone or alcohol the ni-cholestenone forms long needles of M. P. C. and shows a, specific rotation in alcohol of (a) "9=+64.5. It shows an absorption in ultraviolet light of max.: 230 mu, e=10,800. By degradation of the side chain in i'l-position by known means it is transformed to Ai-androstendime-3,17. I

Example 2 320 mgs. of 2-bromo-allo-pregnandione are refluxed for 2 /2 hours with 4 cos. of collidine. After cooling, the collidine hydrobromide separated is drostenol-1'7-one-3-acetate which removed by filtration and washed with ether. The filtrate is mixed with dilute hydrochloric acid and extracted with ether. The ethereal solution is washed with dilute hydrochloric acid and with water, dried with sodium sulfate and evaporated. The residue is recrystallized from alcohol and yields 130 mgs. of m-allo-pregnendione or M. P. 192-l96 C. By repeated recrystallisation the melting pointrises to 201-203 C. This substance when mixed with Am-allo-pregnendione, shows a depression of the melting point of about 30 C. It may be transformed into ni-androstendione by known methods.

Example 3 685 mgs. of 2-bromo-androstandione-3,l7 are refluxed with 7 cos. of collidine for 2 hours. After cooling, the solution is poured into 2 N hydrochloric acid and extracted with ether. The

ethereal solution is washed several times with dilute hydrochloric acid and with water. After evaporation, the residue forms a yellow oil, which crystallises on treating with a small amount of acetone. After recrystallisation from hexane and from dilute acetone 214.2 mgs. 01' A1 androstendione-3,1'7 are obtained of M, P. 138-139" C. in a yield of about 40%. Its specific rotation is (a) =-|-148.5. Its absorption spectrum 1 max =230 m in alcohol, e=10,800. 36 mgs. of A1-androstendione-3,17 are heated with hydroxylamine-acetate, prepared from 80 mgs. of hydroxylamine hydrochloride and 120 mgs. of sodium acetate, for 2 hours in alcohol. The dioxime formed is precipitated from the mixture by addition of water and recrystallized from dilute alcohol. Yield 14.2 mgs. oi. Ai-androstendione-3,1'l-dioxime of M. P. 258-264 C. with decomposition.

Erample 4 813 mgs. of 2-bromo-androstanol-17-one-3- acetate of M. P. I'M-178 C. are boiled with 4 cos. of collidine for 1 hour. After cooling, the mixture is poured into 70 cos. of 2 N hydrochloric acid and extracted with ether. The ethereal solution is washed with N hydrochloric acid, then with water and dried. The remainder after.

evaporation is a darkly coloured oil. It isdissolved in hexane and filtered through aluminium oxide according to Brockmann, From the hexane filtrate and from the benzene extract a colourless residue is obtained consisting of Ai-ancrystallizes from dilute acetone in a yield of 419.5 mgs. M. P. ll'7-l18 C.

For purification it is sublimated under 12 mm. pressure at about-220 C, and recrystallised from dilute acetone.- Then its melting point is 122 C. and its specific rotation (at) 2a=+4'7.2 in alcohol.

58.5 mgs. of said compound are boiled for 30 minutes with 20 cos, of 0.5 N potassium hydroxide solution in alcohol in order to sapo'nify the same. The solution is diluted with water, neutralized and extracted with ether. The residue from the ethereal solution is recrystallized from a mixture of acetone and hexane and from dilute acetone.

Yield 28.6 mgs. of A1-androstenol-17-one-3, leaflets of M. P. 150 C. Specific rotation (e) '=+53.3 in alcohol. Absorption spectrum A max.=230 mu in 8.1001101. e=10,000.

On testing according to Fussganger on the capon's comb, 5 times 0.5 y are sufficient to cause an increase of the area of the comb of 30%. Tested according to Butenandt and Tscherning 2 injections of 300 7 each cause an .ni-androstandione so obtained.

increase of the area of the comb of about 20%. 8 times 250 y injected subcutaneously restore the seminal vesicles of infantile male rats to the stage of secretion. This shows, that m-androstenolone belongs to the most active compounds of the androsterone series.

30 mgs. of A1-androstenol-17-one-3 are oxidized in 5 cos. of glacial acetic acid with 10.4 mgs. of chromic acid for minutes at room temperature. Then the mixture is poured into water and extracted with ether. From the neutral parts by recrystallisation from dilute acetone 8.1 mgs, of A1-androstendione-3,17 are recovered melting at 138-139 C. and showing a specific rotation of (a) =+144.0 in alcohol.

Example 5 4 gs. of 2-bromo cholestanone are boiled with freshly distilled 2,4-dlmethyl pyridine of boiling point -156 C. After a short period of time the mixture begins to become greenish, but no crystals precipitate at boiling temperature. 0n cooling, the dimethyl pyridinium hydrobromide, which is readily soluble in water, crystallizes. The mixture is diluted with ether and thoroughly shaken with dilute hydrochloric acid. Then the ethereal solution is washed with sodium carbonate solution and water. The dark residue remaining after evaporation of the ether is distilled in a high vacuum at -180" C. The pale yellow distillate crystallizes from alcohol. It is the Ai-cholestenone, melting at 95 C. after repeated recrystallisation.

It may be stated that the constitution of the A1-keto-3-steroids obtained according to' this invention is not absolutely certain. Since these compounds, however, show an absorption in the ultraviolet of A max.=230 m e=10,000 in ethanol, which is characteristic for a ni-unsaturated steroidketone they may be defined as true Aicompounds, while the hitherto known A1-keto-3- steroids may be termed "hetero-Ar-keto-3-steroids.

Of course, many changes and variations may be made in the reaction conditions, the starting materials employed, the solvents used, the reaction temperature and duration, the methods of isolating and purifying the reaction products, and so forth by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

What I claim is:

1. Process for the manufacture of Ai-steroidketones-3 comprising heating a 2-halogeno steroid ketone-3 with a higher boiling pyridine base tion product.

2. Process according to claim 1, wherein the 2- halogeno steroid ketone-3 is boiled with collidine.

3. Process according to claim 1, wherein 2- bromo-allo pregnandioneis employed as starting material. I v

4. Process according to claim 1, wherein 2-halogeno andr0stan0l-17-one-3 is employed as starting material.

5. Process for the manufacture of Ar-androstendione comprising heating a Z-haIogeno-androstandione-3,17 with collidine at substantially the boiling point of the latter, and isolating the 6. Process for the manufacture of Ai-androstendione-3,17, which comprises heating 2-bromo- 5' androstandione-3,17 with collidine at substantially the boiling point of the latter, and isolating' the A1-androstendione-3,17 so obtained.

, A1-3-keto compound from the reaction product.

8. A1-androstendione-3,1'7 of M. P. 138-139 C. and of high physiological activity as a male sexual hormone, and having a specific rotation of (a) =+144.0 in alcohol, its dioxime melting at about 258-264: C. with decomposition, its steric configuration corresponding to that produced by the action of a member of the group consisting of collidine and 2,4 dimethyl pyridine at its boiling point on the corresponding 2-bromo compound having a single bond between C1 and C2.

9. Process for the manufacture or A1-androstendione comprising heating a 2-halogenosteroid ketone-3 having a side chain in the 1'7-position with a higher boiling pyridine base at substantially the boiling point of the latter, said base being a member of the group consisting of collidine and 2,4-dimethyl pyridine, splitting off the 25 stendione comprising heatin a z-halogeno-androstandione-3.1'7 with a higher boiling pyridine base at substantially the boiling point 0! the latter, said base being a member of the group consisting of collidine and 2,4-dimethyl pyridine, and isolating the Ai-androstendione so obtained.

11. Process for the manufacture of Ai-androstendione-3,1'7 which comprises heating 2-bromoandrostandione-3,1'7 with a higher boiling pyridine base at substantially the boiling point of the latter, said base being a member or the group consisting of collidine and 2,4-dimethyl pyridine, and isolating the A1-androstendione-3,17 so obtained.

ADOLF BUTENAND'I.

REFERENCES CITED The following references are of record in the file of this patent:

OTHER REFERENCES Marker, Jour. Am. Chem. Soc," vol. 61, pages 1333-1337, June 1939. 

